Cocaine is an alkaloid contained in coca (Erythroxylon coca) leaves a originally came from South America. It causes intense excitation, produces a dependency, and created a serious social problem of cocainism.
Cocaine directly acts on the peripheral sensory nerve fiber to reversively paralyze the same, and shuts down production and conduction of afferent impulses.
The pharmacological actions of cocaine include local anesthesia. Cocaine is advantageous in that it readily penetrates mucous membrane and infiltrates into tissues, and that it causes vasoconstriction to retard its systemic absorption, thereby prolonging anesthesia.
The systemic effect produced by absorption is found in the central nervous system and cardiovascular system. Noticeable excitation proceeds from the upper site to the lower site in the CNS. Thus, at a lower dose, it first acts on the cerebral cortex to manifest mental uplift, the sense of increased intelligence, disappearance of fatigue, euphoria and hyperkinesis. Such condition characterized by feeling of being refreshed and possession of increased mental and physical capabilities is called cocaine drunkenness.
On the other hand, its use in higher doses causes hallucination, derangement, berserk, tremor, clonic spasm, and respiratory excitation, elevation of blood pressure and body temperature, emesis and the like, all of which are caused by stimulation of medulla oblongata, and which in turn progress into suppression (e.g., coma), suppression of respiratory and cardiac functions and suppression of reflex mechanism of spinal cord. When continuously used, psychopathic symptoms such as anxiety, agrypnia, hallucination, delusion, derangement and the like, and physical symptoms of mydriasis, tachycardia, fervescence, convulsion and the like are observed. The mydriasis is also caused by peripheral(sympathetic) action of cocaine. Associated with such psychopathic symptoms, cocaine is classified as a narcotic.
As a narcotic, cocaine is characterized by the fact that it seldom shows physical dependency but shows extremely strong psychological dependency.
In a low or medium dose, its action on the cardiac function is secondary, resulting from its primary action on central and peripheral nerves. When a higher dose is intravenously administered, however, it may directly act on the myocardium to cause cardiac dysfunction. There have been also found central and peripheral actions on blood vessels. It inhibits catecholamine uptake at the adrenergic nerve ending and enhances action of norepinephrine on the vascular wall.
A cholinesterase is an enzyme which hydrolyzes choline ester into choline and organic acid. There exist two types of the enzyme in the living body; acetylcholinesterase (true cholinesterase; EC 3.1.1.7) and cholinesterase (serum cholinesterase, pseudocholinesterase; EC 3.1.1.8). The former resides in the nerve tissues, muscles, erythrocytes and the like, and specifically decomposes acetylcholine. The latter is synthesized in the liver and secreted into serum. While its biological role has not been fully elucidated, it decomposes, besides acetylcholine, various choline esters and non-choline esters.
The metabolism of cocaine is complicated, since it depends on various enzyme activities, doses and administration routes. The major metabolites are three compounds; norcocaine, benzoylecgonine and ecgonine methylester.
Given a report on the use of an organophosphate insecticide (cholinesterase inhibitor) for prolongation of cocaine excitement and a report which indicates that the metabolism of cocaine is shifted largely toward benzoylecgonine, but also somewhat toward norcocaine at low cholinesterase activity, Hoffman et al. documented a report which concludes, "when plasma cholinesterase activity is low, 1) metabolism of cocain is slowed and its toxicity is prolonged, 2) metabolism of cocain is shunted away from the nontoxic ecgonine methylester and toward the active metabolite norcocaine or potentially active metabolite benzoylecgonine." They conclude that the both mechanisms in combination enhance cocaine toxicity and that, by reference to recent findings, serum cholinesterase activity is considered to be an important determinant of cocaine toxicity (Journal of Toxicology, Clinical Toxicology, 34 (3), 259-266 (1996)). Therefore, once the serum cholinesterase activity can be improved, the above-mentioned problems will be solved, and the treatment of cocainism will be facilitated.
The present inventors have surprisingly found that a compound having a prolyl endopeptidase inhibitory activity can specifically activate the serum cholinesterase activity. Hence, administration of a compound having a prolyl endopeptidase inhibitory activity to patients will lead to the cure of cocainism.